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Background The impact of COVID-19 on physical and mental health and employment after hospitalisation with acute disease is not well understood. The aim of this study was to determine the effects of COVID-19-related hospitalisation on health and employment, to identify factors associated with recovery, and to describe recovery phenotypes. Methods The Post-hospitalisation COVID-19 study (PHOSP-COVID) is a multicentre, long-term follow-up study of adults (aged ≥18 years) discharged from hospital in the UK with a clinical diagnosis of COVID-19, involving an assessment between 2 and 7 months after discharge, including detailed recording of symptoms, and physiological and biochemical testing. Multivariable logistic regression was done for the primary outcome of patient-perceived recovery, with age, sex, ethnicity, body-mass index, comorbidities, and severity of acute illness as covariates. A post-hoc cluster analysis of outcomes for breathlessness, fatigue, mental health, cognitive impairment, and physical performance was done using the clustering large applications k-medoids approach. The study is registered on the ISRCTN Registry (ISRCTN10980107). Findings We report findings for 1077 patients discharged from hospital between March 5 and Nov 30, 2020, who underwent assessment at a median of 5·9 months (IQR 4·9–6·5) after discharge. Participants had a mean age of 58 years (SD 13); 384 (36%) were female, 710 (69%) were of white ethnicity, 288 (27%) had received mechanical ventilation, and 540 (50%) had at least two comorbidities. At follow-up, only 239 (29%) of 830 participants felt fully recovered, 158 (20%) of 806 had a new disability (assessed by the Washington Group Short Set on Functioning), and 124 (19%) of 641 experienced a health-related change in occupation. Factors associated with not recovering were female sex, middle age (40–59 years), two or more comorbidities, and more severe acute illness. The magnitude of the persistent health burden was substantial but only weakly associated with the severity of acute illness. Four clusters were identified with different severities of mental and physical health impairment (n=767): very severe (131 patients, 17%), severe (159, 21%), moderate along with cognitive impairment (127, 17%), and mild (350, 46%). Of the outcomes used in the cluster analysis, all were closely related except for cognitive impairment. Three (3%) of 113 patients in the very severe cluster, nine (7%) of 129 in the severe cluster, 36 (36%) of 99 in the moderate cluster, and 114 (43%) of 267 in the mild cluster reported feeling fully recovered. Persistently elevated serum C-reactive protein was positively associated with cluster severity. Interpretation We identified factors related to not recovering after hospital admission with COVID-19 at 6 months after discharge (eg, female sex, middle age, two or more comorbidities, and more acute severe illness), and four different recovery phenotypes. The severity of physical and mental health impairments were closely related, whereas cognitive health impairments were independent. In clinical care, a proactive approach is needed across the acute severity spectrum, with interdisciplinary working, wide access to COVID-19 holistic clinical services, and the potential to stratify care. Funding UK Research and Innovation and National Institute for Health Research.

Five finalists were selected for the 2021 British Cardiovascular Society (BCS) Young Investigator Award (YIA) from a competitive pool of young researchers. At the virtual BCS meeting in June, each finalist gave a 10-minute oral presentation followed by questions from a panel of independent judges. The prize was established by the Society 20 years ago to “recognise excellence among young researchers intending to pursue a career in cardiovascular clinical medicine or research”.1 Dr Blanca Tardajos Ayllon is a postdoctoral researcher at the University of Sheffield in the Department of Infection, Immunity and Cardiovascular Disease, funded by the British Heart Foundation. She obtained a BSc in Biochemistry at Universidad Autonoma de Madrid (Spain) with a year abroad at the University of York. Later, she completed an MSc in Molecular Medicine at the University of Sheffield where her work focused on the identification of mechanoreceptors that regulate endothelial apoptosis using zebrafish models. Dr Tardajos Ayllon then did her PhD in Cardiovascular Science with Professor Paul Evans. Her PhD, funded by the MRC-DiMeN Doctoral Training Partnership, focused on the role of the NF-κB transcription factor c-Rel in endothelial mechanobiology and atherosclerosis (figure 1). Figure 1 Dr Blanca Tardajos Ayllon. Atherosclerosis is a major cause of death that can lead to heart attack or stroke. It develops in the arteries at …

Imaging in medicine has been revolutionised by technological, computational and research advances over the past decades. Computed tomography (CT), in particular, has seen rapid evolution especially in the field of cardiovascular non-invasive imaging. It is being recognised as the first-line tool for the assessment of stable and unstable disease with diagnostic, prognostic and re-stratification potential. Vascular inflammation is a key component of the atherosclerotic process and has been shown to induce molecular, transcriptional and structural changes to perivascular adipose tissue (PVAT). Being a diverse structure itself, PVAT surrounds the human vessels and is characterised by a highly rich secretome, including, amongst others, adipokines, cytokines, gaseous messengers and miRNAs It is implicated in a bidirectional interplay with the adjacent vascular wall, affecting and being affected by aspects of its biology, mainly inflammation. In this review, we discuss the current status of cardiac CT in imaging vascular inflammation through PVAT phenotyping. LINKED ARTICLES: This article is part of a themed issue on Molecular imaging - visual themed issue. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v178.21/issuetoc.

Background: A routine diagnostic work-up does not identify structural abnormalities in a substantial proportion of patients with idiopathic ventricular arrhythmias (VAs). We investigated the added value of cardiac magnetic resonance (CMR) imaging in this group of patients. Methods: A single-centre prospective study was undertaken of 72 patients (mean age 46 ± 16 years; 53% females) with frequent premature ventricular contractions (PVCs ≥ 500/24 h) and/or non-sustained ventricular tachycardia (NSVT), an otherwise normal electrocardiogram, normal echocardiography and no coronary artery disease. Results: CMR provided an additional diagnostic yield in 54.2% of patients. The most prevalent diagnosis was previous myocarditis (23.6%) followed by possible PVC-related cardiomyopathy (20.8%), non-ischaemic cardiomyopathy (8.3%) and ischaemic heart disease (1.4%). The predictors of abnormal CMR findings were male gender, age and PVCs/NSVT non-outflow tract-related or with multiple morphologies. Patients with VAs had an impaired peak left ventricular (LV) global radial strain (GRS) compared with the controls (28.88% (IQR: 25.87% to 33.97%) vs. 36.65% (IQR: 33.19% to 40.2%), p < 0.001) and a global circumferential strain (GCS) (−17.66% (IQR: −19.62% to −16.23%) vs. −20.66% (IQR: −21.72% to −19.6%), p < 0.001). Conclusion: CMR reveals abnormalities in a significant proportion of patients with frequent idiopathic VAs. Male gender, age and non-outflow tract PVC origin can be clinical indicators for CMR referral.

Funding Acknowledgements Type of funding sources: Foundation. Main funding source(s): UKRI, British Heart Foundation Background Inflammation in the coronaries induces macroscopic changes in perivascular adipose tissue composition, detectable by the pericoronary Fat Radiomic Profile (FRP) on coronary computed tomography angiography (CCTA). Purpose To assess the ability of FRP to stratify cardiac risk in patients with Coronary Artery Calcium (CAC) score below 100 following routine CCTA. Methods 1,575 participants from the CCTA arm of the SCOT-HEART trial (NCT01149590) eligible for image analysis were included. Pericoronary FRP mapping was performed in perivascular adipose tissue segmentations around the proximal sites of the right and left coronary arteries, as previously validated. We first tested the prognostic value of FRP in the sub-cohort of patients with CAC Results In total, 1,032 patients (53.9% female sex) were found with low CAC score (CAC Conclusion In individuals with low CAC scores the Fat Radiomic Profile biormarker significantly improves risk prediction for adverse clinical events beyond the current state-of-the-art. Non-invasive profiling of pericoronary adipose tissue using CCTA-derived FRP captures irreversible changes in perivascular adipose tissue composition associated with chronic vascular inflammation and atherosclerotic disease, and can supplement the traditional anatomical assessment of the coronary vasculature with a functional marker of disease activity.

Background Evidence suggests that adverse outcomes in COVID-19 may be driven by a cytokine-induced vascular inflammatory response, caused by SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2). Aim We aimed to develop a non-invasive method for quantifying cytokine-driven vascular inflammation in patients with acute COVID-19 infection that could allow risk stratification. Methods We developed a platform for rapid development of novel imaging biomarkers of vascular inflammation, by applying quantitative radiotranscriptomics to images from standard Computed Tomography Angiography (CTA). We used this platform to train a radiotranscriptomic signature (C19-RS) from the perivascular space around the aorta and the internal mammary artery, visualized in routine chest CTAs, to best describe cytokine-driven vascular inflammation, defined using transcriptomic profiles from RNA sequencing data from human arterial biopsies. This signature was tested externally in 435 clinically indicated CT pulmonary angiograms (CTPAs) from patients with or without COVID-19 from 3 different geographical regions. Results COVID-19 patients were characterised by significantly higher C19-RS values (adjusted odds ratio of 2.97 [95%CI: 1.43–6.27], p=0.004), while patients infected with the new B.1.1.7 variant (“UK variant”) were also found to have higher C19-RS values compared to those with the original variant, evidence suggestive of higher degrees of vascular inflammation. C19-RS had prognostic value for in-hospital mortality in COVID-19, with hazard ratios of 3.31 ([95%CI: 1.49–7.33], p=0.003) and 2.58 ([95%CI: 1.10–6.05], p=0.028) in two external testing cohorts respectively, after correction for clinical factors and biochemical biomarkers of inflammation (WBC, CRP) and myocardial injury (troponin). Importantly, the corrected HR for in-hospital mortality was 8.24[95%CI: 2.16–31.36], P=0.002 for those who received no treatment with dexamethasone, but only 2.27[95%CI: 0.69–7.55], p=0.18 in those who received dexamethasone after the test, suggesting that anti-inflammatory treatment may be modifying the natural history of COVID-19 infection by improving outcomes specifically in those patients with high vascular inflammation. Conclusions Our study introduces a new radiotranscriptomic signature, C19-RS, extracted from routine CTPAs, trained to detect cytokine-driven arterial inflammation, and demonstrates that vascular inflammation determined in this way has prognostic value in patients with COVID-19. The “UK variant” leads to higher vascular inflammation measured in this way, and the risk associated with COVID-19 arteritis is modifiable by dexamethasone.

Coronary computed tomography angiography (CTA) is a first-line investigation in suspected coronary artery disease ([1][1],[2][2]). Further to the detection of luminal stenosis, coronary CTA can characterize distinct high-risk plaque (HRP) features associated with an increased risk of adverse events

Objectives The purpose of this systematic review was to explore the diagnostic accuracy of various cardiovascular magnetic resonance (CMR) index tests for the diagnosis of acute myocarditis in adult patients. Background Acute myocarditis remains one of the most challenging diagnoses in cardiology. CMR has emerged as the diagnostic tool of choice to detect acute myocardial injury and necrosis in patients with suspected myocarditis. Methods We considered all diagnostic cohort and case-control studies. We searched MEDLINE, EMBASE, Cochrane Library, SCOPUS, and Web of Science up to April 21, 2017. We used the Quality Assessment of Diagnostic Accuracy Studies-2 tool to assess the quality of included studies. PROSPERO registration number CRD42017055778 was used. Results Twenty-two studies were included in the systematic review. Because significant heterogeneity exists among the studies, we only present hierarchical receiver operator curves. The areas under the curve (AUC) for each index test were for T1 mapping 0.95 (95% confidence interval [CI]: 0.93 to 0.97), for T2 mapping 0.88 (95% CI: 0.85 to 0.91), for extracellular volume fraction (ECV) 0.81 (95% CI: 0.78 to 0.85), for increased T2 ratio/signal 0.80 (95% CI: 0.76 to 0.83), for late gadolinium enhancement (LGE) 0.87 (95% CI: 0.84 to 0.90), for early gadolinium enhancement (EGE) 0.78 (95% CI: 0.74 to 0.81), and for the Lake Louise criteria (LLC) 0.81 (95% CI: 0.77 to 0.84). Native T1 mapping had superior diagnostic accuracy across all index tests. The AUC of T2 mapping was greater than the AUC of increased T2 ratio/signal and EGE, whereas ECV showed no superiority compared with other index tests. LGE had better diagnostic accuracy compared with the classic CMR index tests, similar accuracy with T2 mapping and ECV, and only T1 mapping surpassed it. Conclusions Novel CMR mapping techniques provide high diagnostic accuracies for the diagnosis of acute myocarditis and constitute promising successors of the classic elements of the LLC for routine diagnostic protocols.

Funding Acknowledgements Type of funding sources: None. Introduction Cardiac magnetic resonance (CMR) imaging can identify the underlying substrate in patients with ventricular arrhythmias (VAs) and normal echocardiography. Myocardial strain has emerged as a superior index of systolic performance compared to ejection fraction (EF), with an incremental prognostic value in many cardiac diseases. Purpose To assess myocardial deformation using 2-D feature-tracking CMR strain imaging (CMR-FT) in patients with frequent VAs (≥500 ventricular premature contractions (VPC)/24 hours; and/or non-sustained ventricular tachycardia), and structurally normal hearts on echocardiography without evidence of coronary artery disease. Methods Sixty-eight consecutive patients (mean age 46 ± 16 years; 54% female) and 72 healthy controls matched for age and body surface area were included in the study. CMR imaging was performed on a 1.5T Magnetom Avanto (Siemens, Erlangen, Germany) scanner using a standard cardiac protocol. Results CMR showed normal findings in 30 patients (44%), while 16 (24%) had previous myocarditis, 6 (9%) had a diagnosis of non-ischaemic cardiomyopathy (NICM), 15 (22%) were diagnosed with VPC-related cardiomyopathy, and 1 patient had subendocardial infarction [excluded from strain analysis]. Mean left ventricular EF (LVEF) in patients was 62% ± 6% and right ventricular EF 64% ± 6% (vs. 65% ± 3% and 66% ± 4% in controls, respectively). Compared to control subjects, patients with VAs had impaired peak LV global radial strain (GRS) (28.88% [IQR: 25.87% to 33.97%] vs. 36.65% [IQR:33.19% to 40.2%], p Conclusion Peak LV GRS and GCS are impaired in patients with frequent idiopathic VAs and can detect myocardial contractile dysfunction in patients with different underlying substrates. Our findings suggest that LV strain indices on CMR-FT constitute independent markers of myocardial dysfunction on top and independently of EF. Abstract Figure.

Background Obesity is associated with increased cardiovascular risk; however, the potential role of dysregulations in the adipose tissue (AT) metabolome is unknown. Objectives The aim of this study was to explore the role of dysregulation in the AT metabolome on vascular redox signaling and cardiovascular outcomes. Methods A screen was conducted for metabolites differentially secreted by thoracic AT (ThAT) and subcutaneous AT in obese patients with atherosclerosis (n = 48), and these metabolites were then linked with dysregulated vascular redox signaling in 633 patients undergoing coronary bypass surgery. The underlying mechanisms were explored in human aortic endothelial cells, and their clinical value was tested against hard clinical endpoints. Results Because ThAT volume was associated significantly with arterial oxidative stress, there were significant differences in sphingolipid secretion between ThAT and subcutaneous AT, with C16:0-ceramide and derivatives being the most abundant species released within adipocyte-derived extracellular vesicles. High ThAT sphingolipid secretion was significantly associated with reduced endothelial nitric oxide bioavailability and increased superoxide generated in human vessels. Circulating C16:0-ceramide correlated positively with ThAT ceramides, dysregulated vascular redox signaling, and increased systemic inflammation in 633 patients with atherosclerosis. Exogenous C16:0-ceramide directly increased superoxide via tetrahydrobiopterin-mediated endothelial nitric oxide synthase uncoupling and dysregulated protein phosphatase 2 in human aortic endothelial cells. High plasma C16:0-ceramide and its glycosylated derivative were independently related with increased risk for cardiac mortality (adjusted hazard ratios: 1.394; 95% confidence interval: 1.030 to 1.886; p = 0.031 for C16:0-ceramide and 1.595; 95% confidence interval: 1.042 to 2.442; p = 0.032 for C16:0-glycosylceramide per 1 SD). In a randomized controlled clinical trial, 1-year treatment of obese patients with the glucagon-like peptide-1 analog liraglutide suppressed plasma C16:0-ceramide and C16:0-glycosylceramide changes compared with control subjects. Conclusions These results demonstrate for the first time in humans that AT-derived ceramides are modifiable regulators of vascular redox state in obesity, with a direct impact on cardiac mortality in advanced atherosclerosis. (The Interaction Between Appetite Hormones; NCT02094183 )

Introduction: COVID-19 is characterised by severe vascular inflammation. Perivascular adipose tissue (PVAT) has the ability to change its texture in response to vascular inflammation. Hypothesis: Computed Tomography Angiography (CTA)-based radiotranscriptomic phenotyping of PVAT may quantify COVID-19-induced vascular inflammation, predicting clinical outcomes. Methods: In Study 1, RNA sequencing of 60 internal mammary artery (IMA) biopsies from patients undergoing coronary bypass surgery was performed to build a transcriptomic fingerprint similar to that observed in COVID-19. This fingerprint was used to train an extreme gradient boosting algorithm, C19-RS, using CTA-derived radiomic features of PVAT around the IMA and descending thoracic aorta. In Study 2, C19-RS was validated in pulmonary artery CTAs from an independent cohort of 201 patients for COVID-19 detection and test its prognostic value in COVID-19. Results: Unsupervised hierarchical clustering of RNASeq data in Study 1 identified 2 clusters of vascular inflammation ( A ). Machine learning was used to train C19-RS to detect vascular inflammation based on 31 radiomic features. In study 2, 22 deaths and 32 ICU admissions were recorded. Patients with high C19-RS had an OR=3.11[95%CI:1.06-9.85] for COVID-19 adjusted for age, sex, risk factors, hsCRP, WBCC, COPD and CT tube voltage. C19-RS significantly improved the discrimination of a baseline model containing the above variables, for COVID-19 detection (delta[AUC]=0.03, p=0.008, B ). C19-RS was significantly associated with in-hospital death ( C ), and a composite endpoint of in-hospital death and ICU admission, with adjusted HR: 4.29 (95% CI: 1.48-13.52, p=0.009). Conclusion: COVID-19-induced vascular inflammation can be quantified by a radiotranscriptomic signature (C19-RS) derived from CT analysis of PVAT. C19-RS stratifies vascular inflammatory burden in COVID-19, and has striking prognostic value for in-hospital outcomes.

Background Coronary computed tomography angiography (CCTA) provides useful information regarding cardiovascular risk assessment. Key aspects of coronary biology induce changes in perivascular adipose tissue composition, detectable by the pericoronary Fat Radiomic Profile (FRP) index. Purpose We assessed the ability of FRP to further stratify cardiac risk in patients with Coronary Artery Calcium (CAC) scoring below 100 following routine CCTA. Methods The study population consisted of 1,575 participants from the CCTA arm of the SCOT-HEART trial (NCT01149590) with images available and eligible for analysis. Pericoronary FRP mapping was performed in perivascular adipose tissue segmentations around the proximal sites of the right and left coronary arteries, as previously validated. The prognostic potential of FRP was initially tested in a sub-cohort, consisting of patients with Coronary Artery Calcium (CAC) score lower than 100. Further analysis was performed after sub-grouping based on the absence of high risk plaque (HRP) features and obstructive coronary artery disease (CAD). The association with future incidence of major adverse cardiac events (MACE: cardiac mortality or non-fatal myocardial infarction) or a composite endpoint of MACE ± late revascularization (MACE-ReVasc) was assessed using adjusted Cox regression models [adjusted for age, sex, systolic blood pressure (SBP), diabetes mellitus (DM), body mass index (BMI), smoking, CAD (≥50% stenosis), total cholesterol, high-density lipoprotein (HDL), and HRP features]. Results Two-thirds (66%) of the study population were at low-risk according to the CAC score (CAC Conclusion The Fat Radiomic Profile biormarker significantly improves risk prediction for adverse clinical events beyond the current state-of-the-art in individuals with low CAC scores. Non-invasive profiling of pericoronary adipose tissue using CCTA-derived FRP captures irreversible changes in perivascular adipose tissue composition associated with chronic vascular inflammation and atherosclerotic disease, and can improve risk stratification and clinical decision making in low-risk populations. Funding Acknowledgement Type of funding source: Foundation. Main funding source(s): British Heart Foundation, National Institute of Health Research, Oxford Biomedical Research Centre

Introduction Coronary inflammation induces spatial changes in perivascular adipose tissue (PVAT) composition, which can now be detected as spatial changes in PVAT attenuation quantified by the perivascular Fat Attenuation Index (FAI) on coronary computed tomography angiography (CCTA). We assessed the ability of perivascular FAI mapping around the right and left coronary territories to independently stratify future cardiac risk. Methods This was a post-hoc analysis of the CRISP-CT (Cardiovascular RISk Prediction using Computed Tomography) study that included 3912 patients with an average age of 55.7 years (standard deviation [SD]: 13.7 years). Perivascular FAI mapping was performed around the proximal right (RCA) and left anterior descending (LAD) coronary arteries. FAI was calculated based on the weighted average attenuation of PVAT using the CaRi-HEART algorithm, as previously described. The independent association with future incidence of cardiac death was assessed in adjusted Cox regression models. Results Over a median follow-up period of 5.6 years, 74 cardiac deaths were recorded. The cross-sectional association between perivascular FAI around the RCA and LAD at baseline was found to be moderate (R2=0.36, P Conclusion Perivascular FAI around the coronary arteries is characterised by anatomical/regional variability, and its values are affected by the coronary segment interrogated. Non-invasive characterization of coronary inflammation using CCTA-derived FAI should include a comprehensive assessment of both coronary arteries in order to better characterize the inflammatory residual risk of each patient.

Introduction High-risk plaque (HRP) features on coronary computed tomography angiography (CCTA) are indicators of increased cardiac risk. Coronary inflammation induces spatial changes in perivascular adipose tissue (PVAT) composition, which can be quantified with the perivascular Fat Attenuation Index (FAI). We hypothesized that perivascular FAI mapping can further stratify the cardiac risk associated with HRP on CCTA. Methods Individuals from the CRISP-CT (Cardiovascular RISk Prediction using Computed Tomography) study were included (n=3,912, mean age 55.7±13.7 years, 41.1% females). Perivascular FAI mapping was performed around the proximal right coronary artery and was calculated based on the weighted average attenuation of PVAT using the CaRi-HEART algorithm, as previously described. HRP features were defined as the presence of either positive remodelling, low-attenuation plaque, spotty calcification or napkin-ring sign. The association with future incidence of major adverse cardiac events (cardiac mortality or non-fatal myocardial infarction) was assessed using Cox regression models (adjusted for age, sex, epicardial fat volume and coronary artery disease [≥50% stenosis]). Results The prevalence of HRP and high FAI (≥-70.1 Hounsfield Units, as previously validated) was 23.6% (n=923) and 24.3% (n=952), respectively. Over a median follow-up of 5.6 years (25th-75th percentile: 4.0–7.0 years) 91 MACE were recorded. Patients with both HRP features and high FAI (FAI+/HRP+) had a 6.3-fold higher adjusted risk of MACE compared to those with neither of these risk features (HRP-/FAI-). Furthermore, patients without HRP features but with high FAI (HRP-/FAI+) had a 4.9-fold higher adjusted risk of MACE compared to the reference (HRP-/FAI-) group. Conclusion FAI is a stronger predictor of cardiac mortality than high-risk plaques, and there is additive predictive value between plaque morphology and coronary inflammatory burden. There is need for tools to provide comprehensive risk assessment based on CCTA, by extracting, weighting and interpreting all available information from these scans.

Adipose tissue has long been identified as a key regulator of cardiovascular health, secreting a wealth of molecules, including hormones, cytokines, and gaseous messengers, which affect the cardiovascular system in both endocrine and paracrine manners. The diversity of adipose tissue biology has led to a shift in our perception of fat as an entity, highlighting the importance of regional variability. In that context, perivascular adipose tissue, a dynamic structure surrounding most vessels in the human body, and secreting a diverse range of adipocytokines and molecules, is being flagged as a distinct depot exerting crucial effects on the adjacent vascular wall and contributing to the development of atherosclerosis. At the same time, the vascular wall releases signaling molecules that diffuse into the perivascular space, modifying its texture and composition by forcing changes in perivascular fat biology. This bi-directional interplay between the vessels and perivascular fat has enabled significant translational advances, with pericoronary adipose tissue imaging emerging as a promising field in non-invasive visualization of atherosclerosis. This chapter summarizes the current knowledge on aspects of perivascular adipose tissue biology, its interplay with the vascular wall, as well as the diagnostic and prognostic value of its imaging, which aim to revolutionize cardiovascular risk prediction.

Background NADPH oxidase activity is a major source of superoxide anions (O2·−) in the human myocardium, linked with adverse short-term clinical outcomes after cardiac surgery, but its prognostic value for the long-term clinical outcome of these patients is unknown. Purpose To explore the association between NADPH oxidase activity in the human myocardium and the clinical outcome of patients undergoing cardiac surgery. Methods A total of 216 patients from the Oxford Heart Vessels and Fat (OxHVF) cohort were enrolled. Myocardial tissue samples were collected during cardiac surgery and used for RNA isolation and myocardial O2·− quantification using lucigenin-enhanced chemiluminescence (5μmol/L). The specific contribution of NADPH oxidase activity to myocardial O2·− production was quantified as the Vas287021 (40 μmol/L)-inhibitable signal following NADPH (100μmol/L) stimulation (Vas2870 is a NADPH oxidases inhibitor). Malonyldialdehyde and hsCRP levels were measured in plasma isolated from peripheral blood collected pre-operatively. Patients were followed-up for a mean of 2.9±1.4 years for the primary endpoint of cardiovascular mortality. Results Myocardial NADPH oxidase activity was not correlated with systemic oxidative stress (evidenced by malonyldialdehyde, panel A) or systemic inflammation (reflected by hsCRP levels, panel B). NADPH oxidase activity was significantly higher in the cardiovascular death group (panel C) and was associated with cardiovascular (HR [95% CI]: 1.53 [1.10–2.13], p=0.01 per SD increase) but not all-cause mortality (HR [95% CI]: 1.32 [0.96–1.80], p=0.08 per SD increase). This association remained significant after adjustment for EuroscoreII (HR [95% CI]: 1.80 [1.14–2.82], p=0.01 per SD increase). For an optimal cut-off value of 7,920 RLU/sec/mg tissue, patient survival was significantly poorer in the high vs. low NADPH oxidase activity subgroup (panel D). Adding NADPH oxidase activity to the baseline clinical model significantly improved model's performance (panel E). Interestingly, myocardial NOX gene expression levels didn't show any significance in mortality prediction, highlighting the fact that NADPH oxidase activity, rather than enzyme levels, is the key outcomes regulator. Conclusion Increased NADPH oxidase activity in the human myocardium independently predicts high cardiovascular mortality in patients with advanced coronary atherosclerosis. Targeting NADPH oxidase in the human heart may be a rational therapeutic approach. Acknowledgement/Funding BHF, EPSRC

Background Hypothesis-free unbiased -omics approaches have started to revolutionise our understanding of adipose tissue (AT) biology providing an exciting opportunity for the discovery of yet unknown adipokines that drive the currently recognised cross-talk between the AT and the vasculature. Methods: Untargeted metabolic profiling of the secretome of paired thoracic and subcutaneous AT samples from 48 patients undergoing cardiac surgery (OxHVF Study) along with subsequent sphingolipids-targeted quantification were performed using liquid-chromatography mass-spectrometry. Immortalised human aortic endothelial cells (teloHAEC) and human umbilical vein endothelial cells (EA.hy926) were treated exogenously with ceramides for 20 min and superoxide (O2.-) was measured using lucigenin-enhanced chemiluminescence. Results: Metabolomics differential and enrichment analyses highlighted the significant differences in sphingolipids secretion levels between the two fat depots. Higher amount of long and very-long chains ceramides were produced and secreted from the thoracic depot with C16-ceramide representing the most abundant differentially secreted ceramide (figure 1). Compared to the lowest tertile, the middle and highest tertiles of ceramides of thoracic AT were significantly associated with enhanced O2.- production in patients’ vessels (figure 2-A). ThAT and ScAT highest and middle tertiles of ceramides were found to be associated with reduced endothelium-dependent vascular relaxation in response to acetylcholine, a fundamental feature of endothelial dysfunction (figure 2-B). Exogenous treatment of teloHAEC and EA.hy926 with ceramide increased basal O2.- and endothelial nitric oxide synthase (eNOS) uncoupling evidenced by more negative O2.- after addition of L-NAME, an inhibitor of eNOS. Moreover, NADPH-stimulated O2.- generation and Vas2870-inhibitable O2.- were significantly higher in cells pre-treated with ceramide compared to untreated counterparts. Conclusions: In this study, we demonstrate for the first time that sphingolipids, in particular ceramides, secreted from the AT of cardiac patients modulate their vascular redox state and vasomotor tones, the key determinants of dysfunctional endothelium—a hallmark of cardiovascular disease. Conflict of interest None

Background Coronary artery inflammation inhibits adipogenesis in adjacent perivascular fat. A novel imaging biomarker—the perivascular fat attenuation index (FAI)—captures coronary inflammation by mapping spatial changes of perivascular fat attenuation on coronary computed tomography angiography (CTA). However, the ability of the perivascular FAI to predict clinical outcomes is unknown. Methods In the Cardiovascular RISk Prediction using Computed Tomography (CRISP-CT) study, we did a post-hoc analysis of outcome data gathered prospectively from two independent cohorts of consecutive patients undergoing coronary CTA in Erlangen, Germany (derivation cohort) and Cleveland, OH, USA (validation cohort). Perivascular fat attenuation mapping was done around the three major coronary arteries—the proximal right coronary artery, the left anterior descending artery, and the left circumflex artery. We assessed the prognostic value of perivascular fat attenuation mapping for all-cause and cardiac mortality in Cox regression models, adjusted for age, sex, cardiovascular risk factors, tube voltage, modified Duke coronary artery disease index, and number of coronary CTA-derived high-risk plaque features. Findings Between 2005 and 2009, 1872 participants in the derivation cohort underwent coronary CTA (median age 62 years [range 17–89]). Between 2008 and 2016, 2040 patients in the validation cohort had coronary CTA (median age 53 years [range 19–87]). Median follow-up was 72 months (range 51–109) in the derivation cohort and 54 months (range 4–105) in the validation cohort. In both cohorts, high perivascular FAI values around the proximal right coronary artery and left anterior descending artery (but not around the left circumflex artery) were predictive of all-cause and cardiac mortality and correlated strongly with each other. Therefore, the perivascular FAI measured around the right coronary artery was used as a representative biomarker of global coronary inflammation (for prediction of cardiac mortality, hazard ratio [HR] 2·15, 95% CI 1·33–3·48; p=0·0017 in the derivation cohort, and 2·06, 1·50–2·83; p Interpretation The perivascular FAI enhances cardiac risk prediction and restratification over and above current state-of-the-art assessment in coronary CTA by providing a quantitative measure of coronary inflammation. High perivascular FAI values (cutoff ≥–70·1 HU) are an indicator of increased cardiac mortality and, therefore, could guide early targeted primary prevention and intensive secondary prevention in patients.

Purpose/Aim of the Study: Osteoprotegerin (OPG) is an α tumor necrosis factor receptor superfamily glucoprotein that acts as a decoy receptor for the receptor activator of nuclear factor kappa B ligand (RANKL), exerting an antiresoptive bone effect. It was recently shown that OPG/RANKL axis is activated during vascular calcification, contributing to atherosclerotic lesions formation. Additionally, OPG levels are charachterized as an independent risk factor for overall vascular mortality in obese adults. We aimed to investigate OPG levels in children/adolescents with obesity and explore possible relations with obesity-related insulin resistance (IR).A total of 160 participants (85 obese) were enrolled. Participants with obesity underwent an oral glucose tolerance test. IR was evaluated according to the homeostasis model assessment-insulin resistance index. Serum OPG levels were determined.OPG levels did not differ significantly between obese subjects and controls in the total sample (p = 0.133). However, in the adolescents' subgroup, serum OPG levels were significantly increased in obesity (p = 0.019). After stratifying participants according to their IR status, only subjects with both obesity and IR exhibited increased OPG levels compared to controls (p 0.001). Factor analysis further associated OPG levels variation to insulin levels variation and to IR.Obese individuals demonstrate increased serum OPG levels during puberty. Obesity per se is not the potent factor for this increase; indeed, IR accompanying obesity seems to exert a fundamental role in OPG upregulation.